1. Immunodeficiency:  

2. Failure of immune system to protect the host from infectious agents or malignant cells or from autoimmune diseases is known as immunodeficiency.
It may be confined to one or more than one factor or cell of the immune system including complete absence or deficiency of that element.
The immunodeficiencies should be suspected in every 
patient, who develops recurrent, persistent, sever or opportunistic infections. 


3. It is either:
Primary / or / Secondary immunodeficiency.
1- Primary immunodeficiency: It is due to an inherited genetic defect or developmental defect in one of the genes responsible for expression of an immune factor, or impairment of function or absence of immune cells. These defects may interfere with the innate or the adaptive immunity, affecting cellular or humoral immune responses.
These defects may be asymptomatic without giving clinical disease and discovered accidentally or expressed as severe clinical conditions at any stage of patient’s life.

4. 2- Secondary immunodeficiency: It is usually due to impairment of the immune system by external factor as:
Infection e.g.: acquired immunodeficiency syndrome (AIDS)
Exposure to chemical agents as chemotherapy
Exposure to physical agents as nuclear radiation.

5. Primary immunodeficiency (PID):
There are more than 150 different types of primary immunodeficiencies (PIDs) in the world.
Primary T–cells deficiencies:
It usually leads to Combined Immunodeficiency (CID) in which there is defect in both T-cell functions and disruption of antibody immune responses. Examples for primary T-cells immunodeficiencies:
Severe combined immunodeficiency (SCID)
Developmental defects in the thymus
Wiskott-Aldrich Syndrome (WAS)

6. Severe combined Immunodeficiency (SCID):
A family of disorders that make most extreme forms of CID. The defects involved in this syndrome usually include one of these defects:
Defective cytokine signaling in T-cell precursors.
Premature death of the lymphoid lineages.
Defective V (D) J rearrangement in developing lymphocytes
Disruption in pre-TCR or TCR signaling during development of T-cells.

7. Depending on the underlying genetic defect, an individual with SCID may have loss of only T-cells (T-B+) or loss of both T and B cells. In both cases there will be absence or severe depression of the humoral and cellular immune responses, poorly developed thymus and very low number of circulating lymphocytes.
These diseases are either inherited as autosomal recessive or they are X-linked diseases.

8. Baby who has SCID will get repeated infections
Baby who has SCID will get repeated infections. The initial manifestation of the disease is infection by fungi or viruses that are normally dealt with by the cellular immune response. The humoral immune response defects may appear later than 6 months age because of the presence of passive maternal antibodies that are received through the placenta or breast milk.

9. The DiGeorge Syndrome (Congenital Thymic Aplasia)
The thymic epithelium is derived from the third and fourth pharyngeal pouch by the sixth week of gestation. Defect is associated with the deletion of the gene on chromosome 22.
The T-cell deficiency is variable, depending on how badly the thymus is affected.
Affected infants have distinctive facial features; their eyes are widely separated. They also have congenital malformations of the heart or aortic arch and neonatal tetany due to hypoplasia or aplasia of the parathyroid glands.
Treatment is by supportive therapy, or thymic epithelial transplant.

10. Wiskott- Aldrich Syndrome (WAS):
WAS is an X-linked immunodeficiency disease.
Affected males have small, abnormal platelets with thrombocytopenia, which may lead to fatal bleeding.
A boy with WAS develops frequent and severe dermatitis as well as pyogenic and opportunistic infections.
Patient’s serum contains high levels of IgA & IgE, normal levels of IgG and low levels of IgM.
Their T cells are defective in function and collaboration among immune cell is faulty.

11. 2- Primary B-Cells Immunodeficiencies:
There is either complete absence of mature B-cells, plasma cells and Igs. Or / selective absence of certain classes of Igs.
They have risks for recurrent bacterial infections with capsulated streptococci, pneumococci or staphylococci, because Abs. are important for opsonisation and clearance of these M.Os.
They have normal immune response to viral or fungal infections because they usually have normal T-cell immune response.

12. X-Linked Agammaglobulinemia (XLA):
XLA occurs in approximately 1 in 200,000 newborns.
85% of cases are due to mutation in a cytoplasmic Bruton tyrosine kinase (Btk), which is required in transduction through the BCR.
Without functioning Btk the development of B-cells in the bone marrow is arrested at the pro-B to pre-B cell stage and the B-cells in these patients remain in pre-B cells stage and Peripheral B-cells are <1%.

13. Inherited as X-linked recessive pattern immunodeficiency disease and affecting boys mainly and very rare in girls. About half of affected individuals get the disease due to new mutations. Carriers do not have abnormalities in their immune system, but they can pass the altered gene to their children.
Cover of antibiotics and passive Igs are the proposed treatment of the disease.

14. Common Variable Immunodeficiency Syndrome:
There are defects in T cell signalling to B cells with impairment of B-cells response to Ags.
There is reduction of one or more isotype of Abs, but most patients have normal B-cells number.
inherited as autosomal recessive or dominant or due to sporadic mutations. Both males and females are equally affected.

15. Patients have recurrent bacterial infections
Patients have recurrent bacterial infections. The disease may appear early in life or may start late given name: late-onset hypogamaglobulinemia or incorrectly acquired hypogamaglobulinemia.
Patients with CVID should be treated with intravenous immunoglobulins

16. Selective IgA deficiency:
Frequency of disease is 1:700
Unknown genetic cause.
IgA producing B-cells cannot differentiate into plasma cells.
Patients have normal other Igs isotypes
Clinical picture (C.P) is variable from asymptomatic in 70% of cases to severe infections, allergies and autoimmune diseases. GIT and RT (The primary sites for production of IgA) are most common sites to get infected. This wide range of C.P from asymptomatic to severe cases may be due to ability of some patients to substitute IgA by IgM on secretary mucosa.

17. 3- Disruptions of the innate immune system:
A- Primary phagocyte deficiencies (PPD)
These defects are presented by recurrent bacterial and fungal infections of unusual sites usually occur in childhood and milder forms in adulthood.

18. Examples: Leukocyte Adhesion Deficiency type I:
This rare disease is due to deficiency of adhesion molecules CD11a/CD18 (LFA-1), CD11b/CD18 (Mac-1 or CR3) and CD11c/ CD18 (CR4) due to deficiency of CD18 component in these receptors. This disease is characterized by impaired phagocytes migration to the sites of infection in spite off peripheral leukocytosis.
Clinically they have repeated gram positive and negative bacterial infections and fungal infection. Some of patients die within few years and others may reach forties.

19. Chronic granulomatous disease (CGD):
It is due to impairment of the NADPH (nicotinamide adenine dinucleotide phosphate) oxidative pathway that enables the phagocyte to produce superoxide radicals that kill the phagocytosed pathogen. It is either inherited as X-linked in 70% of cases or inherited as autosomal recessive in 30% of cases. Patients suffer from repeated bacterial and fungal infection with formation of small granulomatous masses in the infected tissues.

20. Chediak-Higashi syndrome (CHS):
Autosomal recessive disease with impaired lysosomal transport and storage due to mutations in the lysosomal trafficking regulator gene (LYST) that cause impairment in LYST protein (lysosomal trafficking regulator protein). Patients with CHS develop neutropenia, impairment T-cells, impaired NK-cells and granulocytes. Patients presented with recurrent bacterial infections, blood clotting, pigmentation and neurologic function, photosensitivity, light colour hair and skin. Phagocytes produce giant granules (Diagnostic hallmarks of the disease) but they are unable to kill microorganisms.

21. B- Complement deficiency:
It is either due to deficiency in complement activation factor
Or / deficiency of complement activation regulator.
Deficiency of complement activation factor: It includes deficiency of factors that participate in the activation of one or more of the three sectors of the complement activation system (classical pathway, lectin pathway and the alternative pathway).

22. e.gs: 1- C1q deficiency leads to autoimmune diseases as SLE.
C2, C4 deficiency leads to susceptibility to pneumococcal infections.
MASP-2, MBL, and Ficolins deficiency leads to deficiency of the lectin pathway and increase risk of bacterial infections as pneumococcal infection, Candida albicans and autoimmune diseases.
NB : MASP-2 deficiency transient or permanent may be protective from death due to to DIC or severe meningococcal infections.
MASP-3 deficiency leads to deficiency of the alternative pathway increase risk of meningococcal infection.

23. 3MC syndrome (Mingarelli, Malpeuch, Michels, and Carnevale syndrome): 3MC syndrome is a disorder characterized by unusual facial features and problems affecting other tissues and organs of the body. 3MC syndrome is caused by mutations in the COLLEC11 and MASP1 gene. These genes are thought to help direct the migration of neural crest cells, which give rise to various tissues including many tissues in the face and skull, the glands that produce hormones (endocrine glands), and portions of the nervous system

24. . The COLEC11 gene provides instructions for making a complement activation protein called CL-11, which is one of the recognition molecules of the lectin pathway. MASP1 gene gives arise to three different complement activation proteins, MASP-1, MASP-3, and Map-44 by alternative splicing of the gene. These patients have poor alternative pathway with high risk to get infection with Neisseria meningitides.

25. Deficiency of complement activation regulation factor:
These defects usually lead to over activation of complement system and inflammatory disorders.
aTypical Hemolytic uremic syndrome: disease characterized by micro vascular thrombosis, thrombocytopenia, mechanical hemolytic anemia, acute renal failure and neurological complications. This disease occurs due to over activation of the alternative pathway due to deficiency of FH, FI, MCP-1 or DAF (decay accelerating factor) complement regulators. The first choice of treatment is Eculizumab (humanized anti-C5 monoclonal antibodies).

26. Paroxysmal nocturnal hemoglobinourea (PNH): characterized by destruction of RBCs by complement MAC due to defect in complement regulators as protectin and DAF. Treated by Eculizumab.

27. Hereditary angioedema (HAE): autosomal dominant inherited disease characterized by deficiency of C1INH characterized by over activation of the classical pathway and to lower extent the lectin pathway of the complement system. Signs and symptoms begin around puberty. These patients have recurrent swellings in different places of their bodies which may be fatal if occur in vital organs or respiratory tract. Treated by giving iv C1INH

28. Diagnosis of immunodeficiencies:
Awareness of the condition is most important part of the diagnosis and treatment of PIDs. These tests can be used for diagnosis and assessment of PIDs:
Complete blood counts and blood film.
Serological tests for measurement of levels of cytokines, immunoglobulins and complement factors.
Bone marrow aspirates and examination
Chromosomal analysis and gene study.
Functional tests for immunological cells as T-cells, B-cells and macrophages.

29. Treatment of Primary immunodeficiencies:
The treatment options of PID include:
Replacement of missing protein:
As: Immunoglobines concentrates and monoclonal Abs given i.v. Or S.C. IgG level around 5mg/ml can prevent infections.
IFN- γ replacement approved to be of benefit in CGD
Recombinant adenosine deaminase in SCID.

30. Replacement of missing cell type lineage: by bone marrow transplantation
Replacement of missing gene: gene therapy when single gene is affected
Supportive therapy as effective preventive and therapeutic antibiotics, surgical drainage of abscess, vaccination and hygiene control.
Eculizumab for treatment of complement over activation due to regulator deficiency.

31. Secondary immunodeficiencies
The immune system can be adversely affected by a variety of extrinsic factors including:
Immunosuppressive drugs.
Exposure to harsh environmental conditions as radiation.
Hereditary disorders other than primary immunodeficiencies.
Acquired metabolic disorders such as diabetic mellitus.

32. Perhaps the most well known secondary immunodeficiency is Acquired Human Immunodeficiency Syndrome (AIDS) caused by Human Immunodeficiency Virus (HIV) infection.
The most common cause of immunodeficiency worldwide is severe malnutrition, which affects as much as 50% of the population in some impoverished communities.

33. Extremes of age and neonatal prematurity increase susceptibility to infection
The abnormalities of the immune system induced by secondary immunodeficiencies affect both the innate and the adaptive immunity. Treatment of the primary condition often results in the improvement of the compromised immune components of the disease complex.

34. Immunosenescence: It is a decline of the immune response due to aging
Characterized by:
Weakness of the T cell response with reduced delayed type hypersensitivity reaction.
Decrease in immunoglobulins production against many pathogens
Auto Abs against self antigens are formed but autoimmune diseases are less common

35. Declined responses to vaccines, and may not develop protective immunity after influenza vaccine
5-Allergic disorders and transplant rejection are less common
6- Increases of susceptibility to infections like respiratory tract infection, and UTI. TB and Herpes Zoster may be reactivated.
7- Decline or absence of leukocytosis &pyrexia can be noticed during infection.

36. HIV infection and Acquired immunodeficiency syndrome:
HIV stands for human immunodeficiency virus. It is retrovirus. It attacks the body’s immune system, specifically the CD4+ T-cells. Over time, HIV reduces the number of CD4+ T-cells in the body. Opportunistic infections or cancers will be very common and fatal due to a very weak immune system.
No effective cure exists for HIV. But with proper medical care, HIV can be controlled.
How the virus invades and multiplies inside the CD4+ cells:

37. This process includes two stages:
First stage includes the integration of viral genome into the cellular DNA as following:
HIV gp120 receptor binds to CD4 on target cells
HIV gp41 receptor fuses with the cell membrane receptor CXCR4 or CCR5.
Viral genome and enzymes enters the cells
Viral genome and enzymes will be released inside the cells after removal of all nuclear proteins

38. Reverse transcription of viral single stranded RNA (ssRNA) by the viral reverse transcriptase enzyme occurs to give DNA and form RNA-DNA hybrid
Degradation of the viral RNA and completion of the HIV double stranded DNA (dsDNA OR called cDNA).
The viral DNA will be trans located into the nucleus and integrated into the cell genomic DNA by the help of the viral integrase enzyme.
(please refer to figure: 1(A))

39. Figure 1:
a- insertion of the viral genome into the nuclear DNA
b- synthesis and release of the viral particles

40. The second stage includes the synthesis of the new viral genome:
Transcription of proviral DNA into genomic ssRNA
Viral RNA is exported to cytoplasm
(A)- production of viral precursor proteins by cell ribosomes (B)- viral enzymes change the precursor enzymes into viral proteins

41. Viral RNA and protein will assemble beneath the host cell
mbrane where gp120 and gp41 are inserted.
(A)- the membrane buds out forming viral envelope (B)- release of viral particles to outside the cells
(Please refer to figure 1 (B))

42. Figure 1:
a- insertion of the viral genome into the nuclear DNA
b- synthesis and release of the viral particles

43. Patients with AIDS are susceptible to:
Fungal infections: Candidiasis, Coccidioidomycosis, Cryptococcosis, Histoplasmosis, and Pneumocystis carinii pneumonia (PCP)
Parasitic infections: Cryptosporidiosis, chronic intestinal (greater than one month's duration) and also extra intestinal infection, Toxoplasmosis of brain, Cystoisosporiasis, chronic intestinal (greater than one month's duration) with extra intestinal infections.

44. Viral infections: Cytomegalovirus diseases (particularly retinitis) (CMV), Herpes simplex (HSV): chronic ulcer(s) (greater than one month's duration); or bronchitis, pneumonitis, or esophagitis
Bacterial infections: Tuberculosis (TB), Pneumonia (recurrent), and Salmonella septicemia (recurrent).
Cancers: Kaposi's sarcoma (KS) and Invasive cervical cancer
Brain white matter diseases as Progressive multifocal leukoencephalopathy