2. Leukocytes are the effector cells of the immune system
classes of leukocytes (expanded on in the next slide):
Monocytes – become tissue macrophages
Granulocytes
Neutrophils – phagocytic
Basophils – release cytokines (also, the related mast cells)
Acidophils (eosinophils) – release cytokines
Dendritic cells
Lymphocytes
B-lymphocytes
T-lymphocytes
Null cells (now called innate
lymphoid cells; the most prominent being Natural Killer cells)

3. Cells of the immune system
[not]
phagocytic

4. (from Germann)

5. Lymphoid tissue (and importance of lymph nodes)

6. Which of the below cause flow of lymph fluid through lymph vessels:
Top Hat question
Which of the below cause flow of lymph fluid through lymph vessels:
The lymph nodes serve as pumps
The high flow in the vena cava serves as a vacuum, pulling fluid through lymph vessels
When skeletal muscles contract they constrict lymph vessels increasing the fluid pressure in them
The lymph fluid doesn’t really flow; it is just cells moving along the lymph vessels

7. Which of the below cause flow of lymph fluid through lymph vessels:
Top Hat question
Which of the below cause flow of lymph fluid through lymph vessels:
The lymph nodes serve as pumps
The high flow in the vena cava serves as a vacuum, pulling fluid through lymph vessels
When skeletal muscles contract they constrict lymph vessels increasing the fluid pressure in them
The lymph fluid doesn’t really flow; it is just cells moving along the lymph vessels

8. Innate Immune System:
Phagocytes
Tissue macrophages
Circulating neutrophils
Natural Killer (NK) cells (and other innate lymphoid cells)
Complement Protein System

9. Pathogen-associated molecular patterns (PAMPs)
The general way that the innate immune system recognizes something as foreign
Pathogen-associated molecular patterns (PAMPs)
(also damage-associated molecular patterns or DAMPs)
Pattern recognition receptors (PRRs) – many in the family of TLR or Toll-like receptor
Can be membrane receptors or cytosolic receptors, which require the cell to be infected with the pathogen

10. Phagocytosis!

11. Margination (adhesion molecules, selectins) Attachment (integrins)
Movement of leukocytes (e.g., neutrophils) from blood to site of injury
Margination (adhesion molecules, selectins)
Attachment (integrins)
Diapedesis
Chemotaxis
Diapedesis
Germann 23.3
Sherwood 12-3

12. Opsonization antibodies complement proteins (e.g., C3b) Bacterium
Activated complement
molecule, C3b
(an opsonin)
Receptor specific
for activated C3b
molecule
Phagocyte
Sherwood Figure 12.4
Structures are not drawn to scale.

13. Natural Killer Cells
perforins
fragmentins
(induce apoptosis)
They are targeted to cells lacking markers of ‘self’

14. Inflammation (and other pro-inflammatory cytokines)
Bacterial invasion
or tissue damage
Inflammation
Release of
histamine
by mast cells
(and other pro-inflammatory cytokines)
Increased local
capillary
permeability
Local arteriolar
vasodilation
Increased blood
delivery to
injured tissue
Local
accumulation
of fluid
Redness
Heat
Swelling
Pain
Germann 23.3
Increase in
crucial plasma
proteins, such
as clotting
factors,
in tissue
Increase in
phagocytes
in tissue
Phagocytic
secretions
Sherwood Figure 12.2
Defense against
foreign invader;
tissue repair
Systemic responses,
such as fever

15. Widmaier 18-5
The membrane attack complex:
Sherwood
12-8

16. The only point of this slide is to give you a sense as to the number of proteins involved in the complement protein system and the complexity of their interactions.

17. The complement protein system:
Destroys cells
Opsonizes pathogens
Attracts cells of the immune system
Pro-inflammatory

18. Acquired Immunity:
is directed to a specific foreign substance. Acquired immunity is mediated by lymphocytes, and individual lymphocytes make proteins that allow them to recognize and respond to only one type of foreign substance (known as its cognate antigen).
B Lymphocytes = humoral immunity (antibodies)
T Lymphocytes = cellular immunity

19. Epitope – the portion of the foreign molecule that is recognized
Acquired Immunity:
based on specific recognition of specific foreign molecules – such as the interaction of antibodies with their cognate antigen
Cognate antigen – the foreign molecule that is recognized by the specific antibody or cell surface receptor
Epitope – the portion of the foreign molecule that is recognized
Variable region; binding specificity
constant region; specifies class of antibody
The binding site involves the variable region of both the heavy and light chain
Silverthorn 24.9a,b

20. Development of T lymphocytes and B lymphocytes
B lymphocytes – humoral immunity
T lymphocytes – cellular immunity
Widmaier 18-8

21. B cell receptor
Germann 23.7

22. Silverthorn 24.8

23. Primary (initial) vs. secondary B lymphocyte response
Faster and larger!
Germann 23.9

24. The general structure of antibodies
Antigens
Specific antigen-
binding sites
Fab
The general structure of antibodies
Light chain Fc
Heavy chain
Sherwood Figure 12.11
Antibody

25. Germann

26. Actions of Antibodies

27. Two main classes of lymphocytes
Cytotoxic T lymphocytes
Helper T lymphocytes
Germann 23.11

28. Another set of figures showing the different processing of antigens expressed along with MHC class I versus MHC class II.
[all nucleated cells]
[only antigen presenting cells: dendritc cells, B lymphocytes, macrophages]

29. Coreceptors in TCR Binding
This slide is to make the point that in addition to MHC along with CD4 or CD8, there are many co-receptors that are expressed on different populations of T lymphocytes
Coreceptors in TCR Binding

30. Action of cytotoxic T cell
Widmaier 18-18

31. Central role of Helper T cells in the acquired immune response
Note: for both B and T lymphocytes, clones divide into both memory cells and ‘effector’ cells
Germann 23.12

32. Polarization of CD4+ cells.
Polarization of CD4+ cells. Naive CD4+ T cells polarize into TH1, TH2, or TH17 cells or Tregs.
Ulrich Wenzel et al. JASN 2016;27:
©2016 by American Society of Nephrology

33. Role of dendritic cells as well as CD4+ and CD8+ cells in hypertension.
Role of dendritic cells as well as CD4+ and CD8+ cells in hypertension. Hypertension causes lipid oxidation in dendritic cells (DC) resulting in formation of isoketal adducts of various self-proteins. These isoketal-modified proteins behave like DAMPs and activate dendritic cells. The dendritic cells secrete cytokines such as IL-1, IL-6, and IL-23. In the renal lymph node or other tissues dendritic cells may activate CD8+ and CD4+ T cells that migrate into the kidney. CD8+ T cells release cytotoxins such as perforin and granzyme leading to apoptosis or cell death of peritubular capillaries causing vascular rarefaction. IL-17A and IFN-γ released from TH17 and TH1 activate the renin-angiotensin system and may stimulate or upregulate transport channels in the proximal and distal convoluted tubules, including the sodium hydrogen exchanger 3 (NHE3) and the sodium chloride cotransporter (NCC). Both in turn causes sodium and volume retention. Modified from reference 10.
Ulrich Wenzel et al. JASN 2016;27:
©2016 by American Society of Nephrology

34. Working hypothesis describing the role of immunity in hypertension.
Working hypothesis describing the role of immunity in hypertension. Hypertensive factors such as Ang II, salt, or aldosterone lead to a cascade of events: They directly activate the innate immune system. This process includes complement activation and release of DAMPs, which can activate toll-like receptors and also the inflammasome. On the one hand these mechanisms damage the kidney directly. On the other hand, they promote the release of cryptic antigens and ROS production, isoketal formation, and alteration of proteins in dendritic cells. These nonself recognized proteins are presented to T cells. Polarized CD4+ and CD8+ T cells migrate into the heart, vessels, and kidney and mediate the hypertensive end-organ damage or aggravate this damage, as in the case of kidney arterial hypertension due to salt and volume retention. In addition activation of cells, such as monocytes/macrophages, γδ T cells, NK cells and ILCs may mediate or aggravate hypertensive renal injury. Modified from reference 7. CNS, central nervous system, nAg, neoantigen.
Ulrich Wenzel et al. JASN 2016;27:
©2016 by American Society of Nephrology

36. Renal denervation as a potential treatment for hypertension?48

37. Effect of Renal Sympathetic Denervation on Glucose Metabolism in Patients With Resistant Hypertension Clinical Perspective
Felix Mahfoud, Markus Schlaich, Ingrid Kindermann, Christian Ukena, Bodo Cremers, Mathias C. Brandt, Uta C. Hoppe, Oliver Vonend, Lars C. Rump, Paul A. Sobotka, Henry Krum, Murray Esler, and Michael Böhm
Change in systolic and diastolic office blood pressures (SEM) at 1 and 3 months compared with baseline. P values refer to change in blood pressure compared with baseline. Between-group effects, measured by 2-way repeated measures ANOVA, are given as P for interaction.
Mahfoud F et al. Circulation. 2011;123:
Copyright © American Heart Association, Inc. All rights reserved.

39. So, the SPLIMPLICITY HTN-3 trial did not provide much support for the effectiveness of renal denervation in treatment of hypertension

40. But this trial was limited by various problems, including:
Patients on medication, with possible confound of patients not in compliance with their medication
Lack of completeness of renal denervation

41. Data from the SPYRAL HTN-OFF MED trial:

42. Figure 6. Changes in 24-hour ambulatory mean systolic (sBP) and diastolic (dBP) blood pressure (BP) in resistant hypertensive patients who underwent renal denervation with predominantly distal ablation (distal RDN) as opposed to those with conventional (conv RDN) renal denervation. With permission from the study of Pekarskiy et al.⁶⁸
From: Renal Sympathetic Denervation: A Viable Option for Treating Resistant Hypertension
Markus Schlaich
Am J Hypertens. 2017;30(9): doi: /ajh/hpx033
Am J Hypertens | © American Journal of Hypertension, Ltd All rights reserved. For Permissions, please 42

43. Effects of increased sympathetic activity on peripheral circulation and organs.
Effects of increasedsympathetic activity on peripheral circulation and organs. Sympathetic efferent activation is generated in the central nervous system. Efferent nerves target the heart, vessels, and kidney to produce structural and functional effects. In turn, renal afferents are stimulated after injury or hypoxia by, eg, adenosine acidosis and others and activate afferents deriving back to the central nervous system. Thus, a vicious cycle in the interaction between brain and kidney further enhances sympathetic activation. RAAS indicates renin–angiotensin–aldosterone-system.
Böhm M et al. Circulation Research. 2014;115:
Copyright © American Heart Association, Inc. All rights reserved.